Oxadiazolylimidazobenzodiazepine, compositions, and method

ABSTRACT

The application discloses novel benzodiazepine agonist compounds, namely, 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-halo-4H-imidazo [1,5-a][1,4]benzodiazepines, pharmaceutical compositions thereof, and a method of ameliorating central nervous system ailments therewith, especially convulsions and anxiolytic states. A novel intermediate and process for their production are also disclosed.

BACKGROUND OF INVENTION

1. Field of Invention

This invention relates to novel oxadiazolyl imidazobenzodiazepinecompounds pharmaceutical compositions thereof, method of treatingtherewith, and to methods of preparing such compounds. The novelcompounds are useful in psychopharmaceutical applications, e.g., in thetreatment of central nervous system ailments, for example, as ananti-convulsant or an anxiolytic.

2. Prior Art

It is well known (Squires, R. F. and Braestrup, C., Nature (London) 266,(1977) 734) that specific sites in the central nervous systems ofvertebrates exhibit a high specific affinity for binding 1,4- and1,5-benzodiazepines. These sites are called benzodiazepine receptors.

Ferrosan European patent application 109,921 (published May 30, 1984)and corresponding U.S. Pat. No. 4,507,313 (filed Nov. 15, 1983, issuedMar. 26, 1985) disclose compounds having the general Formula I ##STR1##wherein R' is hydrogen, chlorine, fluorine, or nitro in the 7- or8-position,

R¹ is hydrogen or lower-alkyl of up to 3 carbon atoms,

R³ is an oxadiazolyl of the formula ##STR2## wherein R" is lower-alkylof up to 3 carbon atoms,

A B is a grouping of the formula ##STR3## wherein R⁵ is hydrogen ormethyl, and

R"' is hydrogen or chlorine.

This U.S. Pat. No. 4,507,313 further discloses (Column 1, lines 59through Column 2, line 4) that such oxdiazolyl benzodiazepines of EP No.27,214 (U.S. Pat. No. 4,316,839) column 4, line 2 and oxadiazolylbeta-carbolines, as disclosed in earlier European patent application No.54,507 (U.S. Pat. No. 4,435,403), exhibit stronger binding affinity forthe benzodiazepine receptors than the analogous substituted compoundswhich are alkyl esters (rather than such oxadiazolyl derivatives). RocheEuropean patent application No. 150,040 (published July 31, 1985) andcorresponding Danish patent application No. 245/85 (made available July22, 1984) and the presumed corresponding U.S. patent application alsodisclose oxadiazolyl imidazobenzodiazepines.

The disclosure of Roche European patent application No. 150,040 is verybroad. Its disclosure of 1,2,4-oxadiazolyl-benzodiazepine compounds canbe illustrated by Formulas II and III. ##STR4## wherein R¹ =alkyl,cycloalkyl, methoxymethyl

R³ =H, CH₃, and

R⁴, R⁵ =H, halogen ##STR5## wherein X= ##STR6## wherein R¹ =alkyl,cycloalkyl, CF₃, or methoxymethyl

R⁴, R⁵ =H, halogen, CF₃, and

n=2 or 3.

The compounds of Roche EP No. 150,040 examples 2, 3, 16, and 43 are oldcompounds of Ferrosan U.S. Pat. No. 4,507,313 column 2, lines 5-6, andexamples 2 and 3 are preferred compounds of Roche EP No. 150,040 page 5lines 34-37".

The compounds of Roche EP No. 150,040 examples 2, 3, 16, 29, 32, 43, 44,45, 49, 50, 51, 52, 53, and 56 are5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine compounds.

The compounds of Roche EP No. 150,040 examples 1, 8, 9, 17, 18, 23, 30are 10, 11, 12,12a-tetrahydro-9-oxo-9H-imidazo[1,5-a]azeto[2,1-c][1,4]benzodiazepinecompounds.

The compounds of Roche EP No. 150,040 examples 4, 5, 6, 7, 10, 11, 12,13, 14, 15, 19, 20, 21, 22, 24, 25, 26, 27, 28, 31, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 46, 48, 54, 55, 57, 58 and 59 are 11, 12, 13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepinecompounds.

The compound of Roche EP No. 150,040 example 47 is an11,13a-dihydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepinecompound.

The compounds of Roche EP No. 150,040 examples 11, 15, 26, and 40 are1,2,4-oxadiazol-3-yl compounds.

The compounds of Roche EP No. 150,040 examples 11, 15, 26, and 40 are1,2,4-oxadiazol-3-yl compounds combined with an 11, 12, 13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepineskeleton.

The compound of Roche EP No. 150,040 Example 40 is a5-cyclopropyl-1,2,4-oxadiazol-3-yl compound with an11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepineskeleton.

The compound of Roche EP No. 150,040 Example 40 is a5-cyclopropyl-1,2,4-oxadiazol-3-yl compound which has been found grosslyinferior in pharmacological and biochemical evaluations as furtherreported hereinafter.

Of specific interest to the present invention, the Roche patentapplication EP No. 150,040 discloses the following compounds ##STR7##wherein ##STR8##

Roche European patent application No. 150,040 further claims a processfor the preparation of such compounds (II and III) by reacting compoundsof Formula IV and V ##STR9## wherein R⁴, R⁵ and n have the meanings setforth in the foregoing and Y is a leaving group, with a compound of theformula

    CN--CH.sub.2 --X

wherein X has the meaning set forth in the foregoing for Formula III.

All oxadiazoles in the Roche application are actually made by reactingintermediates IV or V with CN--CH₂ --CO₂ R to form a compound of FormulaIV or V having the additional substituent in place of Y wherein X is CO₂R, which is thereafter, in several steps, converted to an oxadiazole.

The new compounds provided by the present invention have the same typeof structure and activity as disclosed in the prior art, but theparticular and specific compounds of the present invention, and theparticular and specific "subject matter as a whole", including not onlytheir chemical structure but also their pharmacological properties, havebeen found to be both advantageous and unobvious from the standpoint ofone skilled in the art.

OBJECTS

It is an object of the present invention to provide novel3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-halo,especially 7-chloro- and 7-bromo-4H-imidazo[1,5-a][1,4]benzodiazepinesand pharmaceutically-acceptable acid addition salts thereof, which areuseful in the treatment of central nervous system disorders or ailments,especially as anticonvulsants and anxiolytics, a process for producingthe same, pharmaceutical compositions thereof, an intermediate therefor,and a method of treating therewith. Additional objects will becomeapparent hereinafter, and still others will be obvious to one skilled inthe art.

SUMMARY OF THE INVENTION

The invention, in summary, comprises the following: A compound selectedfrom the group consisting of3-(5-cyclopropyl-1,2,4-oxdiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-halo,especially 7-chloro- and 7-bromo-4H-imidazo[1,5-a][1,4]benzodiazepinesand pharmaceutically-acceptable acid addition salts thereof; apharmaceutical composition suitable for use in the treatment of centralnervous system ailments, especially convulsions and anxiety states,comprising an effective amount of such3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-halo-4H-imidazo[1,5-a][1,4]benzodiazepineor a pharmaceutically-acceptable acid addition salt thereof, a method oftreating such ailments or disorders in a subject in need thereofcomprising the step of administering to the subject an amount of such3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-halo-4H-imidazo[1,5-a][1,4]benzodiazepineor a pharmaceutically-acceptable acid addition salt thereof effectivefor such purpose; and such a method wherein the active compound isadministered in the form of a pharmaceutical composition containing alsoa pharmaceutically-acceptable carrier or diluent. The invention alsocomprises a method of synthesizing the compounds of the invention, and anew intermediate therefor.

The free basic compounds of the present invention have the formula##STR10##

M.p. chloro--165.1°-169.2° C. bromo--212°-213° C.

These compounds can be prepared either by conventional methods analogousto the methods described in Ferrosan U.S. Pat. No. 4,507,313 Example 3,Roche EP No. 150,040 Example 40, or Schering U.S. Pat. No. 4,435,403Example 70 as illustrated below ##STR11## or by the new method providedby the present invention and as illustrated below ##STR12## wherein Y isa leaving group, such as the --OP(O)(O-ethyl)₂ group of Example 6hereof. Alternatively, the leaving group may be any disclosed in U.S.Pat. Nos. 4,031,079 or 4,359,420, for example, halogen, alkylthio, e.g.,methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto,--OP(O)(OR)₂ wherein R is lower-alkyl or --OP(O)(NR'R") wherein R' andR" each represents lower-alkyl, allyl, or phenyl, or together with thenitrogen atom to which they are attached represent a heterocyclicradical such as morpholino, pyrrolidino, piperidino, ormethylpiperazino. The reaction is preferably carried out under alkalineconditions, i.e., in the presence of a base, and among bases alkalimetal, e.g., potassium or sodium, alkoxides or hydrides are preferred.The reaction is preferably conducted in the presence of an organicsolvent which is nonreactive with the reactants and products of reactionunder the conditions of reaction, especially an anhydrous solvent andpreferably an anhydrous aprotic solvent such as dimethylformamide (DMF)or the like. The temperature range employed may be any range suitablefor the reaction to proceed at a reasonable rate and without undue delayor decomposition and a range from a minus forty (-40) degrees Celsius toabout room temperature is accordingly usually particularly suitable.

PHARMACEUTICAL COMPOSITIONS

The compound of the invention, together with a conventional adjuvant,carrier, or diluent, and if desired in the form of apharmaceutically-acceptable acid addition salt thereof, may be placedinto the form of pharmaceutical compositions and unit dosages thereof,and in such form may be employed as solids, such as tablets or filledcapsules, or liquids, such as solutions, suspensions, emulsions,elixirs, or capsules filled with the same, all for oral use, in the formof suppositories for rectal administration; or in the form of sterileinjectable solutions for parenteral (including subcutaneous) use. Suchpharmaceutical compositions and unit dosage forms thereof may compriseconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and such unit dosage formsmay contain any suitable effective central nervous system ailmentalleviating (or benzodiazepine agonistic) amount of the activeingredient commensurate with the intended daily dosage range to beemployed. Tablets containing ten (10) milligrams of active ingredientor, more broadly, ten (10) to thirty (30) milligrams, per tablet, areaccordingly suitable representative unit dosage forms.

The compound of this invention can thus be used for the formulation ofpharmaceutical preparations, e.g., for oral and parenteraladministration to mammals including humans, in accordance withconventional methods of galenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral or oral applicationwhich do not deleteriously react with the active compound.

Examples of such carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salt for influencing osmotic pressure,buffers and/or coloring substances and the like, which do notdeleteriously react with the active compound.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Ampoules are conveniently unit dosages.

For oral application, particularly suitable are tablets, dragees, orcapsules having talc and/or a carbohydrate carrier or binder or thelike, the carrier preferably being lactose and/or corn starch and/orpotato starch. A syrup, elixir or the like can be used when a sweetenedvehicle can be employed. Generally, as to broader ranges, the compoundof the invention is dispensed in unit dosage form comprising 0.05-100 mgin a pharmaceutically-acceptable carrier per unit dosage.

METHOD OF TREATING

Due to its high degree of affinity for the benzodiazepine receptors, thecompound of the invention is extremely useful in the treatment ofcentral nervous system ailments or disorders, when administered in anamount effective for the alleviation, amelioration, or eliminationthereof, which is of course also a benzodiazepine agonistic amount. Theimportant CNS activity of the compound of the invention includes bothanticonvulsant and anxiolytic activities along with a low toxicity,together presenting a most favorable therapeutic index. The compound ofthe invention may accordingly be administered to a subject, e.g., aliving animal body, including a human, in need of the same for thetreatment, alleviation, amelioration, or elimination of an indication,associated with the central nervous system and the so-calledbenzodiazepine receptors, which requires such psychopharmaceuticaltreatment, e.g., especially convulsion and/or anxiety states, if desiredin the form of a pharmaceutically-acceptable acid addition salt thereof(such as the hydrobromide, hydrochloride, or sulfate, in any eventprepared in the usual or conventional manner, e.g., evaporation todryness of the free base in solution together with the acid), ordinarilyconcurrently, simultaneously, or together with apharmaceutically-acceptable carrier or diluent, especially andpreferably in the form of a pharmaceutical composition thereof, whetherby oral, rectal, or parenteral (including subcutaneous) route, in aneffective psychopharmaceutical central nervous system ailmentalleviating amount, e.g., an anticonvulsant and/or anxiolytic amount,and in any event an amount which is effective for the alleviation ofsuch a central nervous system ailment due to its benzodiazepineagonistic effect. Suitable dosage ranges are 1-200 milligrams daily,preferably 10-100 milligrams daily, and especially 30-70 milligramsdaily, depending as usual upon the exact mode of administration, form inwhich administered, the indication toward which the administration isdirected, the subject involved and the body weight of the subjectinvolved, and the preference and experience of the physician orveterinarian in charge. Broader ranges for dosages of the compoundaccording to this invention are 0.1-300 mg/day, preferably 1-30 mg/day,when administered to patients, e.g., humans, as a drug.

DETAILED DESCRIPTION OF THE INVENTION

The following Examples are given by way of illustration only, but arenot to be construed as limiting.

Example 15,6-dihydro-5-methyl-6-oxo-7-chloro-4H-imidazo[1,5-a][1,4]benzo-diazepine-3-carboxamideoxime

A mixture of 1.2 g3-cyano-5,6-dihydro-5-methyl-6-oxo-7-chloro-4H-imidazo[1,5-a][1,4]benzodiazepine(prepared as in U.S. Pat. No. 4,316,839), 0.45 g of hydroxylaminehydrochloride, 20 ml of 99% ethanol, 2 ml water, and 1.2 g potassiumcarbonate was refluxed for 11/2 hours. The reaction mixture was filteredand the filtrate was concentrated. The residue was treated with 50 ml ofwater and the crystalline solid was filtered off and washed with water.

M.p. 227.6°-228.4° C.

Example 23-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-chloro4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 580 mg5,6-dihydro-5-methyl-6-oxo-7-chloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamideoxime as prepared in Example 1 and 0.3 ml of cyclopropyl carboxylic acidchloride was stirred in 15 ml THF for two hours at 20° C. andevaporated. After evaporation 20 ml of acetic acid was added and themixture was refluxed for 21/2 hours and then evaporated. The reactionmixture was allowed to stand overnight at room temperature, whereafterthe mixture was cooled, filtered, and the filtrate evaporated to give aresidue as oily crystals.

The residue was treated with ether to give the title compound as palecrystals which were collected by filtration.

M.p. 165°-169° C.

Example 3 Formylaminomethyl-carboxamideoxime

To 53.6 g/0.638 mol/N-formylamino-acetonitrile* was added 0.55 molfreshly liberated hydroxylamine dissolved in 370 ml methanol. An icebath was used to keep the temperature below 20° C. during the addition.The solution was allowed to stand at room temperature overnight,whereafter it was evaporated to give the title compound as palecrystals.

Decomp. 104°-110° C.

Example 4 3-Formylaminomethyl-5-cyclopropyl-1,2,4-oxadiazole

A mixture of 35 ml ethylcyclopropyl carboxylate, 30 gformylaminomethyl-carboxamideoxime, 1 g sodium and 30 g crushed molsieves (4 Å) was refluxed in 300 ml abs. EtOH for 8 hours whereafter afurther 1 g sodium was added. The reaction mixture was filtered and thefiltrate was evaporated. The dark oily residue was suspended in 300 mlCHCl₃, filtered and the filtrate was evaporated to give the titlecompound as an oil.

H-NMR (60 MHz, CDCl₃) σ (ppm): 1.2 (4 H, m), 2.8 (1 H, m), 4.5 (2 H, d,j=6 Hz), 7.8 (1 H, broad-NH), 8.2 (1 H, s).

Example 5 5-Cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole

A stirred solution of5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) andtriethylamine (176 mmol) in CH₂ Cl₂ (100 ml) was charged dropwise withPOCl₃ (60 mmol) at 0° C., whereafter a solution of Na₂ CO₃ (60 mmol) inH₂ O (50 ml) was added. The mixture was heated to room temperature,whereafter the organic phase was separated, dried and evaporated invacuo. The residue was treated with ether, decanted and the solution wasevaporated to give the title compound as an oil.

The oil was processed without any further purification. IR: cm⁻¹ : 2160.

Example 63-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-chloro-4H-imidazo[1,5-a][1,4]benzodiazepine

3,4-dihydro-4-methyl-6-chloro-2H-1,4-benzodiazepine-2,5(1H) dione (U.S.Pat. No. 4,316,839) (9.17 mmol) was dissolved in dry DMF (20 ml) andcharged with sodium hydride (10 mmol). The resulting solution was cooledunder N₂ to -20° C., whereafter chlordiethylphosphate (11 mmol) wasadded.

The reaction mixture was kept under N₂ with stirring at -20° C. andcharged with a -30° C. cold solution of5-cyclopropyl-3-isocyanomethyl-1,2,4-oxdiazole (11 mmol) andK-t-butylate (11 mmol) in dry DMF (15 mmol).

The resulting reaction mixture was allowed to heat to room temperature,whereafter it was evaporated to dryness in vacuo. The oily residuecontaining the crude product was purified on SiO₂ with ethyl acetate aseluent. This gave the title compound as white crystals.

M.p. 165°-168.5° C.

Example 73-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-bromo-4H-imidazo[1,5-a][1,4]benzodiazepine

2.5 g of 3,4-dihydro-4-methyl-6-bromo-2H-1,4-benzodiazepine-2.5(1H)dione (8.5 mmol) was dissolved in dry DMF (30 ml) and charged with 480mg sodium hydride. The resulting solution was cooled under an atmosphereof N₂ to -20° C., whereafter chlordiethyl-phosphate (1.6 ml) was added.

The reaction mixture was kept under N₂ with stirring at -20° C. and wascharged with a -30° C. cold solution of5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazol (1.64 g) and K-t-butylate(1.23 g) in dry DMF (15 ml).

The resulting reaction mixture was allowed to heat to room temperatureand was stirred for 30 minutes. The crude product was precipitated byaddition of 150 ml water. This crude product was partitioned between 50ml ethylacetate/diethylether (1/1) and 100 ml 4M hydrochloric acid. Theorganic phase was discharged and the product was precipitated byneutralizing the aqueous phase with 2M sodium hydroxyde. Theprecipitated product was crystatized from ethylacetate. This gave thetitle compound as white crystals.

M.p. 212°-13° C.

Example 8 Representative Pharmaceutical Compositions

(a) A typical tablet for use in treating anxiety states and which may beprepared by conventional tableting techniques contains

    ______________________________________                                        Compound of Invention*                                                                              1.0 mg                                                  Lactosum (lactose)   67.4 mg Ph. Eur.                                         Avicel ® (microcellulose)                                                                      31.4 mg                                                  Amberlite ® (IRP 88)**                                                                          1.0 mg                                                  Magnesii stearas      0.25 mg Ph. Eur.                                        (magnesium stearate)                                                          ______________________________________                                         *possibly salt form                                                           **ion exchange resin                                                     

Exactly the same tablet may be used for treating convulsions.

(b) For suppositories, any usual suppository base may be employed forincorporation thereinto by usual procedure of the active ingredient,such as a polyethyleneglycol which is a solid at normal room temperaturebut which melts at or about body temperature.

(c) for parenteral (including subcutaneous) sterile solutions, theactive ingredient together with conventional ingredients in usualamounts are employed, such as sodium chloride, sodium dihydrogenphosphate, disodium edetate (ethylenediaminetetraacetic acid disodiumsalt), benzyl alcohol, sodium hydroxide to adjust pH, anddouble-distilled water q.s., according to conventional procedure, suchas filtration, aseptic filling into ampoules, and autoclaving forsterility.

Other suitable pharmaceutical compositions will be immediately apparentto one skilled in the art.

PHARMACOLOGY

The compounds of the invention have been found to exhibit anunpredictably favourable and highly advantagenous degree of activity inthe standard classical test for determining the in vivo affinity for thebenzodiazepine receptors, as well as in the standard test consideredpredictive for pharmaceutical activity against convulsions and anxietystates mediated through the benzodiazepine receptors.

The following test has been performed on the compound of the inventionas well as on representative examples of prior art compounds.

I. In vivo inhibition of ³ H-flunitrazepam binding to mouse forebrainmembranes by test substances administered intraperitoneally (Procedure130)

Principle

Twenty minutes after a dose of ³ H-flunitrazepam (³ H-FNM) (200 μCi/kg,i.v.) the amount of specific ³ H-FNM binding to brain benzodiazepinereceptors has reached its maximal value. This specific binding of ³H-FNM can be partly or completely prevented by simultaneous or prioradministration of pharmacologically active brenzodiazepines and by somebenzodiazepine-like agents (Chang and Snyder, Eur.J.Pharmacol. 48,212-218 (1978)).

Test procedure

Suspensions of test substances (2 mg/ml) are prepared in 5% Duphasol-X*by sonification for 10 min using a Branson B15 microtip ultrasonifier(setting 7). Groups of three mice (female, NMR, 18-22 gram) are injectedwith the test substance at 100 mg/kg intraperitoneally. Fifteen minutesafter test substance administration the mice are challenged with 4 μCiintravenously of ³ H-FNM (70-90 Ci/mole) in 200 μl physiological saline.Twenty minutes after ³ H-FNM administration mice are sacrificed bydecapitation, the forebrains rapidly excised (within 30 sec) andhomogenized in 12 ml of icecold 25 mM KH₂ PO₄, pH 7.1, using anUltra-Turrax homogenizer fitted with an N 10 shaft. Two aliquots of 1 mlare immediately filtered through Whatman GF/C glassfibre filters andwashed with 2×5 ml of the above mentioned buffer. The amounts ofradioactivity on the filters are determined by conventionalscintillation counting. One group of untreated mice serves as controls.One to three mice are injected with 25 mg/kg clonazepam i.p. 30 minutesbefore ³ H-FNM to determine the amount of non-specific ³ H-FNM binding,which should be between 8-15% of total binding.

When doses of 100 mg/kg inhibit more than 50% of specific ³H-flunitrazepam binding; test substances are administered in doses,which are factors of 3.16 times lower than 100 mg/kg.

The ED₅₀ for a test substance is defined as that dose which inhibits 50%of specific ³ H-FNM binding. Specific binding is the amount of bindingin controls minus the amount binding in clonazepam-treated mice.

Results

The ED₅₀ value is determined from dose response curves. If only one doseof test substance is administered the ED₅₀ value is calculated asfollows, provided that the inhibition of specific binding is within therange of 25-75%: ##EQU1## where C_(o) is specific binding in controlsand C_(x) is specific binding in mice treated with test substance.

II. Pentazol clonic conv. mice (i.p.) (Procedure 400)

Principle

Pentylenetetrazol induces clonic and tonic convulsions in mice at dosesof 60-120 mg/kg s.c. The mechanism is unknown but seems to be due tosome effects through the GABA receptor/benzodiazepine receptor/chlorideionophore complex. Antagonism of convulsions induced by maximal doses ofpentylenetetrazol is considered predictive for drugs effective againstpetit mal epilepsia and anxiety.

Method

150 mg/kg pentylenetetrazol dissolved in 0.9% NaCl is given by thesubcutaneous route in volumes of 15 ml/kg to male or female NMRI miceweighing 20-25 g 30 min after an intraperitoneal injection of a testcompound. Number of mice exhibiting clonic seizures is noted within thenext 30 min. At least 3 doses of each test compound are used with 4 or 8mice per dose, and with doses both above and below the ED₅₀ value.

Results

The ED₅₀ value is calculated as the dose in μg/kg at which seizures areinhibited in 50% of the animals using a computer program based on themethod of Litchfield and Wilcoxon (1949).

III. Pentazol tonic conv. mice i.p. (Procedure 401)

Principle

Pentylenetetrazol induces clonic and tonic convulsions in mice at dosesof 60-120 mg/kg s.c. The mechanism is unknown but seem to be due to someeffects through the GABA receptor/benzodiazepine receptor/chlorideionophore complex. Antagonism of convulsions induced by maximal doses ofpentylenetetrazol is considered predictive for drugs effective againstpetit mal epilepsia and anxiety.

Method

150 mg/kg pentylenetetrazol (Pentazol, Sigma) dissolved in 0.9% NaCl isgiven by the subcutaneous route in volumes of 15 ml/kg to male or femaleNMRI mice weighing 20-25 g 30 min after an intraperitoneal injection ofa test compound. Number of mice exhibiting tonic seizures is notedwithin the next 30 min. At least 3 doses of each test compound are usedwith 4 or 8 mice per dose, and with doses both above and below the ED₅₀value.

Results

The ED₅₀ value is calculated as the dose in μg/kg where seizures areinhibited in 50% of the animals using a computer program based on themethod of Litchfield and Wilcoxon (1949).

THE TABLE

Test results obtained by testing the compound of the invention and thecompounds considered to be the closest prior art will appear from thefollowing Table 1.

    __________________________________________________________________________     ##STR13##                                                                     ##STR14##                                                                             R.sup.4                                                                           R.sup.5                                                                            X        ED.sub.50 μg/kgbindingin vivo                                                     clonictonicED.sub.50 μg/kgconvulsions                                     entazol inducedActivity                      __________________________________________________________________________                                     against                                       ##STR15##                                                                            H   CH.sub.3                                                                            ##STR16##                                                                             27     40    3                                       ##STR17##                                                                            H   CH.sub.3                                                                            ##STR18##                                                                             15      2   0.2                                      ##STR19##                                                                            H   CH.sub.3                                                                            ##STR20##                                                                             1,800  27,000                                                                             1.300                                    ##STR21##                                                                            H   CH.sub.3                                                                            ##STR22##                                                                             200    600  200                                      ##STR23##                                                                            H   CH.sub.3                                                                            ##STR24##                                                                             60     90    30                                      ##STR25##                                                                            CH.sub.2 CH.sub.2 CH.sub.2                                                              ##STR26##                                                                             960    13,000                                                                             1,000                                   __________________________________________________________________________     .sub.--A Compound of the Present invention                                    .sub.--B Compound of Ferrosan USP 4,507,313 ex. 3                             .sub.--C Compound of Ferrosan USP 4,507,313 column 2, line 6                  .sub.--D Compound of Roche EP 150,040 ex. 29                                  .sub.--E Compound of Roche EP 150,040 ex. 40                             

From above table it is readily apparent that the compound of theinvention is remarkably and unpredictably superior in every respectcompared to the most structurally closely-related compounds of the priorart.

In direction comparison to its corresponding3-cyclopropyl-1,2,4-oxadiazol-5-yl analogue (D) of Roche EP No. 150,040(ex. 44) the chloro compound of the invention is more than 2 times asactive in binding affinity for the benzodiazepine receptor,approximately 21/4 times as active in protecting against pentetrazolinduced clonic convulsions, and 10 times as active in protecting againstpentetrazol induced tonic convulsions.

In direct comparison to the compound E having exactly the samesubstituted oxadiazol-3-yl substituent the chloro compound of theinvention is 35 times more as active in binding affinity for thebenzodiazepine receptor, 325 times as active in protecting againstpentetrazol induced clonic convulsions, and 330 times as active inprotecting against pentetrazol induced tonic convulsions.

In direct comparison to the compound E having exactly the samesubstituted oxadiazol-3-yl substituent the bromo compound of theinvention is 60 times more as active in binding affinity, 6500 times asactive in protecting against pentetrazol induced clonic convulsions, and5000 times as active in protecting against pentetrazol induced tonicconvulsions.

In conclusion, from the foregoing, it is apparent that the presentinvention provides a novel anticonvulsant and anxiolytic3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-halo-4H-imidazo[1,5-a][1,4]benzodiazepinesand addition salts thereof, having highly advantageous and unpredictableproperties.

Further, a new synthesis is provided by the present invention as well asa new intermediate therefor.

It is to be understood that the invention is not to be limited to theexact details of operation, or to the exact compositions, methods,procedures, or embodiments shown and described, as obvious modificationsand equivalents will be apparent to one skilled in the art, and theinvention is therefore to be limited only by the full scope of theappended claims.

We claim:
 1. A3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-halo-4H-imidazo[1,5-a][1,4]benzodiazepinehaving the formula ##STR27##
 2. A compound of claim 1 which is3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-chloro-4H-imidazo[1,5-a][1,4]benzodiazepine.3. A compound of claim 1 which is3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-bromo-4H-imidazo[1,5-a][1,4]benzodiazepine.4. A pharmaceutical composition suitable for use in the treatment of acentral nervous system ailment comprising an amount of a compound ofclaim 1, 2, or 3 which is effective for the alleviation of such disordertogether with a pharmaceutically-acceptable carrier or diluent.
 5. Amethod of treating a central nervous system ailment in a subject in needof such treatment comprising the step of administering to the saidsubject an amount of a compound of claim 1, 2, or 3 which is effectivefor the alleviation of such ailment.
 6. A method of treating a centralnervous system ailment in a subject in need of such treatment comprisingthe step of administering to the said subject an amount of a compound ofclaim 1, 2, or 3 which is effective for the alleviation of such ailmentin the form of a pharmaceutical composition thereof, in which it ispresent together with a pharmaceutically-acceptable carrier or diluent.